A Phase III Trial Comparing FULV to FULV + A Phase III Trial Comparing FULV to FULV + Oxaliplatin in Stage II or III Carcinoma of the Oxaliplatin in Stage II or III Carcinoma of the
Colon: Results of NSABP-C-07Colon: Results of NSABP-C-07
Norman Wolmark, MDColorectal Cancer Update Think Tank Meeting
June 24, 2005
RandomizeRandomize
LV5FU2
Stage ll+lll
FOLFOX4
MOSAICMOSAIC
0 10 20 30 40 50
23% risk reduction in the FOLFOX arm
DFS (months)
Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01
3-yearFOLFOX (n = 1,123) 77.8%LV5FU2 (n = 1,123) 72.9%
1.0
0.9
0.8
0.7
0.6
0.5
Pro
po
rtio
n o
f p
atie
nts
Source: de Gramont A. Presentation. ASCO 2003.
DFSDFS
On November 4, 2004, the FDA approved oxaliplatin in combination with infusional FULV for
adjuvant Stage III colon cancer. The approval was based on improvement in DFS…
RandomizeRandomize
FULVBolus 5-FU/leucovorin
Stratification: Number of positive nodes
FLOXBolus 5-FU/leucovorin
+ oxaliplatin
Stage ll+lll
NSABP-C-07NSABP-C-07
NSABP-C-07: 5-FU/LV versus 5-FU/LV plus NSABP-C-07: 5-FU/LV versus 5-FU/LV plus Oxaliplatin in Stage II/III Colon CancerOxaliplatin in Stage II/III Colon Cancer
x 3
LV
R
Week 1 2 3 4 5 6 7 8
FU
LV
FU
500
500
500
500
OHP 85 2hr
Re
st
Re
st
Source: Wolmark N. Presentation. ASCO 2005.
NSABP-C-07NSABP-C-07
Opened: 02-00
Closed: 11-02
Accrual: 2,407
MTS: 34 mo.
Endpoint: 3 yr DFS
Event: first recurrence, second primary, death (any cause)
89% power to detect: 5.4% ↑ DFS
Source: Wolmark N. Presentation. ASCO 2005.
C-07C-07AccrualAccrual
FULV FLOX
RandomizedIneligible/Lost
1,24538
1,24747
Analysis 1,207 1,200
Source: Wolmark N. Presentation. ASCO 2005.
C-07C-07Patient CharacteristicsPatient Characteristics
Age FULV % FLOX %
<6060-6970+
50.433.016.6
52.431.915.7
Location FULV % FLOX %
Left ColonRight ColonSigmoidMultiple + Unk
20.841.536.81.9
19.845.732.61.9
Positive Nodes FULV % FLOX %
01-3≥4
28.845.725.3
28.944.825.6
Source: Wolmark N. Presentation. ASCO 2005.
Grade FULV FLOX
0-IIIIIIVV
494191
3850101
Source: Wolmark N. Presentation. ASCO 2005.
C-07C-07Overall Toxicity (%)Overall Toxicity (%)
C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity
Gr I P/D that do not interfere with function
Gr II P/D interfering with function, but not ADL
Gr III P/D with pain or interference with ADL
Gr IV Persistent P/D that are disabling or life-threatening
Source: www.eloxatin.com/hep/patientmgmt5.asp
P = paresthesia; D = dysesthesia; ADL = activities of daily living
Grade ≥ 1 (All) Neurotoxicity (%)
During Tx
100
80
60
40
20
0
C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity
Grade > 1 (All) Neurotoxicity (%)
During Tx 12 months
100
80
60
40
20
0
85.4 85.4
29.4
Source: Wolmark N. Presentation. ASCO 2005.
C-07 Sanofi-NCI NeurotoxicityC-07 Sanofi-NCI Neurotoxicity
Grade III Neurotoxicity (%)
10
8
6
4
2
0
8
0.5
During Tx 12 months
Source: Wolmark N. Presentation. ASCO 2005.
OxaliplatinOxaliplatinProtocol-Stipulated Cumulative DoseProtocol-Stipulated Cumulative Dose
C-07 765 mg/m2
MOSAIC 1,020 mg/m2
Source: Wolmark N. Presentation. ASCO 2005.
73% received protocol-stipulated cumulative dose
1 2 3
100
80
60
40
20
0
Percent of Full Dose Oxaliplatin/CyclePercent of Full Dose Oxaliplatin/Cycle
86.9
68.662.5
Source: Wolmark N. Presentation. ASCO 2005.
N
FULV 34 (2.7%)
FLOX 56 (4.5%)
Source: Smith RE et al. Proc ASCO GI 2004.
C-07C-07Bowel Wall InjuryBowel Wall Injury
C-07C-07Deaths During TreatmentDeaths During Treatment
N
FULV 14 (1.1%)
FLOX 15 (1.2%)
Source: Wolmark N. Presentation. ASCO 2005.
1.0
0.9
0.8
0.7
0.6
0.5
Pro
po
rtio
n o
f p
atie
nts
0 1 2 3 4
21% risk reduction
p < 0.004HR: 0.79 [0.67 – 0.93]
C-07 C-07 Disease-Free SurvivalDisease-Free Survival
Events 3y DFSFLOX 272 76.5%FULV 332 71.6%
Source: Wolmark N. Presentation. ASCO 2005.
Years
The global test for interaction between treatment and
tumor stage (II+III) was not significant (p = 0.70).
Benefit from Oxaliplatin in NSABP-C-07 and Benefit from Oxaliplatin in NSABP-C-07 and MOSAIC TrialsMOSAIC Trials
3y DFS Δ HR
C-07 76.5% 4.9% 0.79
MOSAIC 77.9% 4.9% 0.77
Sources: Wolmark N. Presentation. ASCO 2005; de Gramont A. Presentation. ASCO 2003.
ConclusionsConclusions
The addition of oxaliplatin to weekly bolus FULV significantly improves 3-year DFS in patients with Stage II and III colon cancer.
The data confirm and extend the results of the MOSAIC trial.
The benefit of oxaliplatin does not appear to be dependent on the schedule of FULV administration.
The data support the use of weekly bolus FULV in combination with oxaliplatin in adjuvant colon cancer.
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